Journal article
PI3K regulates TAZ/YAP and mTORC1 axes that can be synergistically targeted
JCI insight, Vol.11(6), e191600
03/23/2026
DOI: 10.1172/jci.insight.191600
PMCID: PMC13043097
PMID: 41678521
Abstract
Sarcomas are a heterogeneous group of cancers with few shared therapeutic targets. We show that PI3K signaling is frequently activated in sarcomas due to PTEN loss (in 30-60%), representing a common therapeutic target. The PI3K pathway has lacked a downstream oncogenic transcription factor. We show TAZ and YAP are transcriptional co-activators regulated by PI3K and drive a transcriptome necessary for tumor growth in a PI3K-driven sarcoma mouse model. This PI3K-TAZ/YAP axis exists in parallel to the known PI3K-Akt-mTORC1 axis providing a rationale for combination therapy targeting the TAZ/YAP-TEAD interaction and mTORC1. Combination therapy using IK-930 (TEAD inhibitor) and everolimus (mTORC1 inhibitor) synergistically diminished proliferation and anchorage dependent growth of PI3K-activated sarcoma cell lines at low, physiologically achievable doses. Furthermore, this combination therapy showed a synergistic effect in vivo, suggesting that an integrated view of PI3K and Hippo signaling can be leveraged therapeutically in PI3K activated sarcomas.
Details
- Title: Subtitle
- PI3K regulates TAZ/YAP and mTORC1 axes that can be synergistically targeted
- Creators
- Keith C Garcia - University of IowaAli A Khan - University of IowaKrishnendu Ghosh - University of Iowa, PathologySouradip Sinha - University of IowaNicholas Scalora - University of IowaGillian DeWane - University of IowaColleen Fullenkamp - University of IowaNicole Merritt - University of IowaYuliia Drebot - University of IowaSamuel Y Yu - University of IowaMariah Leidinger - University of IowaMichael D Henry - University of IowaPatrick J Breheny - University of IowaMichael S Chimenti - University of IowaMunir R Tanas - University of Iowa
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.11(6), e191600
- DOI
- 10.1172/jci.insight.191600
- PMID
- 41678521
- PMCID
- PMC13043097
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- American Society for Clinical Investigation
- Grant note
- NIHVeterans Health Administration Merit Review Program: 1 I01 BX003644-01 NIH, National Cancer Institute (NCI): 1 R01 CA237031-01A1 NCI: 1 R01 CA237031-01A1S1 University of Iowa Stead Family Scholars ProgramUniversity of Iowa Sarcoma Multidisciplinary Oncology Group pilot awardCenter for Biocatalysis and Bioprocessing Predoctoral FellowshipNCI Core grant: P30 CA086862
This work is the result of NIH funding, in whole or in part, and is subject to the NIH Public Access Policy. Through acceptance of this federal funding, the NIH has been given a right to make the work publicly available in PubMed Central. center dot Veterans Health Administration Merit Review Program (1 I01 BX003644-01, to MRT) . center dot NIH, National Cancer Institute (NCI) (1 R01 CA237031-01A1, to MRT) . center dot NIH, NCI (1 R01 CA237031-01A1S1, to KCG and MRT) . center dot University of Iowa Stead Family Scholars Program (to MRT) . center dot University of Iowa Sarcoma Multidisciplinary Oncology Group pilot award (to MRT) . center dot Center for Biocatalysis and Bioprocessing Predoctoral Fellowship (to AAK) . center dot NCI Core grant P30 CA086862 (University of Iowa Holden Comprehensive Cancer Center) .
- Language
- English
- Electronic publication date
- 02/10/2026
- Date published
- 03/23/2026
- Academic Unit
- Molecular Physiology and Biophysics; The University of Iowa Institute for Vision Research; Pathology; Biostatistics; Iowa Institute of Human Genetics
- Record Identifier
- 9985139314702771
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